The purpose of this application for support from the NIH Molecular Libraries Roadmap program on the topic of "Accelerated Approaches to Hetero- and Carbocyclic Scaffolds" is to exploit new methodologies previously discovered in the PI's laboratories for the efficient synthesis of chemically diverse Pilot-Scale Libraries for High-Throughput Screening. We propose to generate 4 small molecule libraries of 100-1,000 distinct chemical compounds each, for a total of 2,100 samples, to be submitted to the MLSMR over a period of 3 years. We exclusively target scaffolds that are far underrepresented in the MLSMR. The proposed 3 heterocyclic as well as 1 bridged carbobicyclic ring systems have a high likelihood of modulating the function of biomacro-molecules due to their similarity to natural products or heterocyclic drugs, but contain novel or exceedingly rare core structures. Specifically, we intend to pursue the following goals: 1. Preparation of libraries based on the 5,6-dihydro-2H-1,2,6-thiadiazine 1,1-dioxide heterocyclic chemotype. 2. Preparation of libraries based on the 4H-pyrimido[1,2-a]pyrimidine heterocyclic chemotype. 3. Preparation of libraries based on the 5-sulfonyl-pyrimidine-2,4(1H,3H)-dione heterocyclic chemotype. 4. Preparation of libraries based on the bicyclo[3.3.1]nonane carbobicyclic chemotype. 5. Efficient follow up on the synthesis of 2nd generation libraries for any hits identified in MLPCN HTS campaigns, in close collaboration with the MLPCN and the assay providers. The major strengths of this application are (a) the medicinal chemistry relevance of the proposed scaffolds, which include both heterocyclic, carbobicyclic, and natural product-like structures that currently are poorly if at all represented in the MLSMR, as well as, (b) the track record of the PI in the successful parallel synthesis of libraries of 50-500 members of well characterized organic compounds on multi-milligram scale, including the shipping and handling of these samples to the screening community and the proactive interactions with multiple biological collaborators.